Improving vaccination strategies and understanding and treatment of infectious diseases require identification and quantification of variables that determine the ability of the immune system to respond to an antigenic challenge. A particular challenge is the aging immune system where the ability to mount adaptive immune responses to vaccinations and viral infections declines. Variables that determine the outcome of an immune response and are sensitive to aging include the repertoire of antigen-specific T and B cells; the robustness of homeostatic control mechanisms; the ability of cells to migrate to the site of antigen exposure; the activation threshold of responding cell population; the availability of and responsiveness to nonspecific stimuli; and the ability of responding T and B cell population to proliferate and differentiate. We will perform immune profiling before and after VZV vaccination to identify signatures that correlate with successful T and B cell vaccine responses. The overreaching hypothesis is that comparison of vaccinated individuals of different age groups and patients with zoster reactivation will allow defining underlying mechanisms that can be used to target interventions to compensate for defective pathways. In Specific Aim 1, we will perform a twin study to examine the influence of age and inherited factors on frequency, phenotype and repertoire of VZV-specific T cells in naturally acquired VZV immunity. Specific Aims 2 and 3 propose a longitudinal study of the VZV vaccine response in different age groups. Specific aim 2 will focus on the early immune response to define the factors that correlate with a rapid and diverse T cell response. Specific Aim 3 proposes to identify T cell signatures at peak response that correlate with T cell memory development and antibody production. In Specific Aim 4, we identify patients with zoster reactivation in two at-risk groups, patients with the autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus and patients older than 60 years. Signatures obtained in these patients during active herpes zoster infection will be compared to the vaccination-induced signatures.